Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency. Thus, analgesics with high usefulness and reduced tendency to cause drug dependency are desired. Considerable pharmacological and biochemical studies have been carried out to discover the opioid peptides and opioid receptors, and the discovery of the subtype of opioid receptor such as .mu., .delta., .kappa. at a peripheral nerve in a variety of species, including human, has made a beginning towards creating new analgesics. As it is thought that opioid analgesics such as morphine act as a Preceptor agonist, separating the action based on a .kappa.-receptor agonist from the action based on .mu.-receptor agonist has been investigated. Recently .kappa.-selective agonists have been reported from the above viewpoint for example, EMD-60400: A. Barber et al., Naunyn-Schmled. Arch. Pharmacol., 345 (Suppl.): Abst 456. Some of them have been studied in clinical trials (Med. Res. Rev., 12, 525 (1992)).
WO 96/30339 describes a compound of the formula: ##STR1## and the salt thereof, wherein A is hydrogen, hydroxy or OY, wherein Y is a hydroxy protecting group;
Ar is phenyl optionally substituted with one or more (preferably up to three) substitutents selected from halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CF.sub.3, C.sub. 1-C.sub.4 alkoxy-C.sub.1 -C.sub.4 alkyloxy, and carboxy-C.sub.1 -C.sub.4 alkyloxy; PA1 X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1-tetralone-6-yl, C.sub.1 -C.sub.4 alkylenedioxy, pyridyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, NO.sub.2, CF.sub.3 and SO.sub.2 CH.sub.3 ; and PA1 R is hydrogen, C.sub.1 -C.sub.4 alkyl or a hydroxy protecting group. PA1 2-(3,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)- phenylethyl] acetamide; PA1 2-(4-Bromophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-pheny lethyl] acetamide; PA1 N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-2-(4-trofl uoromethylphenyl)acetamide; PA1 2-(4-Chlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phen ylehtyl]acetamide; PA1 2-(2,3-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)- phenylethyl]acetamide; PA1 2-(2,4-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)- phenylethyl]acetamide; PA1 2-(2,5-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)- phenylethyl]acetamide; PA1 2-(2,6-Dichlorophenyl)-N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)- phenylethyl]acetamide; PA1 N-Hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yI)-1-(S)-phenylethyl]-2-(2,3, 6-trichlorophenyl)acetamide; PA1 2-(3,4-Dichlorophenyl)-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethy l]acetamide; and PA1 2-(3,4-Dimethylphenyl)-N-hydroxy-N-[2(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-p henylethyl]acetamide. PA1 Ar is phenyl optionally substituted with one or more (preferably up to three) substitutents selected from halo, hydroxy, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, CF.sub.3, C.sub.1 -C.sub.4 alkoxy-C.sub.1 -C.sub.4 alkyloxy, and carboxy-C.sub.1 -C.sub.4 alkyloxy; PA1 X is phenyl, naphthyl, biphenyl, indanyl, benzofuranyl, benzothiophenyl, 1-tetralone-6-yl, C.sub.1 -C.sub.4 alkylenedioxy, pyridyl, furyl and thienyl, these groups optionally being substituted with up to three substituents selected from halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, NO.sub.2, CF.sub.3 and SO.sub.2 CH.sub.3 ; and PA1 R is a benzyl group.
The hydroxamic acid derivatives of formula (I), wherein A is hydrogen or hydroxy and R is hydrogen or C.sub.1 -C.sub.4 alkyl, exhibit significant agonist activity toward opioid .kappa.-receptor. Therefore these .kappa. agonists are particularly useful as an analgesic agent in mammals, especially humans. They are also useful as antiinflammatory, diuretic, anesthetic or neuroprotective agents, or an agent for treatment of stroke or functional bowel diseases such as abdominal pain, for the treatment of a mammalian subject, especially a human subject.